Gastrointestinal symptoms in children
The respiratory system appears to be the main target of SARS-CoV-2;
however, numerous evidence supports the fact that the gastrointestinal
tract and the liver may also be involved both in children as well as in
adults.4 This involvement can be associated with
isolated modifications of some laboratory parameters (for example, liver
enzymes) or with overt symptoms. In adults, the reported incidence of
diarrhea varies from 2% to 50% of cases, and the overall percentage of
diarrhea was estimated to be 10.4%.5
In children, the available data are sparse, however gastrointestinal
symptoms, including nausea, vomiting, diarrhea, and abdominal pain, seem
to occur frequently. Diarrhea and vomiting have been reported in about
8-9% of cases, reaching more than 20% in some studies (Table 1).
Therefore, although COVID-19 in children seems to have a milder course
than in adults and respiratory symptoms are less frequently reported,
the incidence of gastrointestinal symptoms is similar to that observed
in adults.
Unfortunately, both in adult and pediatric studies, the characteristics
of diarrhea are not usually reported, and information related to the
total number of evacuations, consistency of the stools, and duration of
symptoms is poor. On one study, diarrhea appeared 1 to 8 days after the
onset of the disease, with a median of 3.3 days.4Watery diarrhea appears to be more frequently reported. Bloody diarrhea,
probably associated with SARS-CoV-2 colitis, has been described only in
one adult patient so far.6 Few adult cases of
esophagitis are also reported.7
Some children presented with diarrhea or vomiting as the first symptom
of the disease, even before or in the absence of respiratory
manifestations. For example, there are some case reports of infants or
older children who developed fever and diarrhea as the only or main
manifestation of the disease.8 Thus, it is currently
discussed whether, in the course of an epidemic, diagnostic tests for
SARS-CoV-2 in children presenting with diarrhea alone or associated with
fever should be considered.9 Furthermore, the fact
that, in some cases, gastrointestinal symptoms may precede systemic and
respiratory ones support the hypothesis that the gastrointestinal system
represents a possible route of viral invasion and transmission.
In adult case-series, gastrointestinal symptoms have been reported to be
associated with more severe disease.7,10 In a
systematic review, diarrhea was found to be more common in patients with
severe forms of COVID-19 than those with the non-severe disease (5.8%
vs. 3.5%, respectively) and patients with diarrhea, nausea and vomiting
were more likely to develop acute respiratory distress or to require
mechanical ventilation compared to patients without gastrointestinal
symptoms (6.76% vs. 2.08%, p = 0.034). However, other studies did not
confirm this finding with gastrointestinal symptoms occurring at a
similar rate in patients with severe and not-severe
forms.10 The discrepancies among study results may be
influenced by several factors, including the variable proportion of
patients with diarrhea observed in the various studies and by the fact
that some antiviral drugs, likely used in more severe cases, include
diarrhea as a possible adverse event (e.g., lopinavir/ritonavir). To
date, a possible correlation between the presence of diarrhea and the
severity of COVID-19 does not seem to be found in
children.4 In a recent Chinese study on 244 SARS-CoV-2
infected children, authors compared disease severity between 34 (13.9%)
children with at least one gastrointestinal symptom (diarrhea, nausea,
vomiting, abdominal pain, decreased feeding) with those without
gastrointestinal involvement. Patients with gastrointestinal symptoms
were younger (14 vs. 86 months; p<0.05) and were more likely
to have a fever on admission (70.6% vs. 35.7%, p<0.05), but
no other significant differences were found between the two groups,
including respiratory symptoms, the duration of RT-PCR positivity for
SARS-CoV-2 and lung radiology findings.11
As regards liver involvement, a modest increase in liver enzymes is well
described in the pediatric population, with varying percentages among
studies, ranging from 13% to 50%. In two pediatric studies reporting
two datasets in Italy and China, overall including over 270 children,
increased serum levels of aspartate aminotransferase (> 50
U/L) (20.4-50% of cases) were more frequently observed than increased
in alanine aminotransferase serum levels (> 45 U/L)
(13-35% of cases).12 This data, together with the
fact that the increase in transaminases is often associated with the
increase in creatine kinase and lactic dehydrogenase serum levels,
suggests that hypertransaminasemia may be an expression of myositis than
liver damage in many cases.4
However, in children, a severe increase in serum liver enzymes is
considered a warning sign. This recommendation is mainly based on data
obtained from adult studies that report increased serum liver enzymes
being more frequent in severe COVID-19 cases (40-60%) than in mild or
asymptomatic forms (18-25%).4 Abnormal bilirubin
levels may also occur, although to a lesser extent than increases in
alanine aminotransferase and aspartate aminotransferase.
The pathogenesis of liver damage in adults is complex ad related to
direct viral invasion, systemic inflammation, hepatic ischemia, and
hypoxia. Liver involvement may be part of multiorgan failure in the
context of a multisystem inflammatory disorder. Moreover, pre-existing
liver disease and drug-related liver toxicity may play a
role.13
ACE-2 expression may be enriched in cholangiocytes, indicating that
SARS-CoV-2 might directly bind to these cells to dysregulate liver
function. Gamma-glutamyltransferase, a biomarker for cholangiocyte
injury, has been elevated in 30 (54%) of 56 patients with COVID-19 in
one adult study.13
In pediatrics, however, it should be bared in mind that severe COVID-19
forms are exceptional and in children with SARS-CoV-2 infection and
abnormalities in liver function tests, investigation for possible
etiologies of liver or muscle damage other than SARS-CoV-2 should be
considered.4